1. Field of the Invention
The present invention relates to a method for preparing nondeliquescent, crystalline calcium pantothenate. In addition, the present invention relates to nondeliquescent, crystalline calcium pantothenate which is substantially free from an organic solvent, and relates to a method for preparing thereof.
2. Description of Background Information
Calcium pantothenate (monocalcium bis[(R)-N-(2,4-dihydroxy-3,3-dimethylbutyryl)-xcex2-alaninate]; hereinafter occasionally abbreviated as xe2x80x9cPCxe2x80x9d) is a medicament listed in the Japanese Pharmacopoeia and widely used for prophylactic and therapeutic treatment of pantothenic acid deficiency as well as therapeutic treatment of contact dermatitis, acute and chronic eczema and the like. This substance is highly dissolvable in water, and when the substance is heated in the state of an aqueous solution, a purity of the substance will be reduced by hydrolysis. Accordingly, a method of spraying an aqueous solution and drying the resulting particles with hot air to produce a product in an amorphous form, or a method of precipitating crystals from a methanol solution, and collecting the precipitates by filtration and then drying with warm air to obtain an amorphous product have been used as methods for a large-scale manufacture of a product with a high purity. However, there is a problem that the amorphous products are hygroscopic and they will receive deiquescence with absorption of moisture at use to give solidified powders.
As crystals of calcium pantothenate, xcex1-type, xcex2-type, and xcex3-type crystals have been known so far, as well as 4CH3OH.1H2O solvate and monohydrate as crystals added with a solvent (see, Inagaki et al., Chem. Pharm. Bull., 24, pp.3097-3102, 1976, with respect to identification and details of each of the crystal forms). Among them, the 4CH3OH.1H2O solvate is hygroscopic and deliquescent. Therefore, it has been desired to develop an industrially applicable method for manufacture of the xcex1-type, xcex2-type, or xcex3-type crystal, or the monohydrate which are nondeliquescent. However, a method which can stably produce any of these nondeliquescent crystals in large quantities and in a convenient manner has not yet been developed.
As for preparation of calcium pantothenate, methods having been proposed include a method comprising the steps of crystallizing PC from an organic solvent such as methanol and dissolving the resulting crystals in water and concentrating the resulting solution, and then adding methanol and heating the mixture to obtain nondeliquescent needles (m.p. 195-196xc2x0 C.) (Levy, H. et al., J. Amer. Chem. Soc., 63, pp.2846-2847, 1941); a method for obtaining crystals from a methanol solution which are different from those obtained by the aforementioned method of Levy et al. (m.p. 153.5-154xc2x0 C.) (Funahashi et al., Report of RIKEN (the Institute of Physical and Chemical Research), 22, 681, 1943); a method comprising the step of adding an appropriate amount of water to a methanol solution to deposit crystals (Japanese Patent Publication No. Sho. 40-2330/1965); a method of depositing an optical active product from a water-containing methanol solution (Japanese Patent Publication No. Sho. 49-27168/1974); a method of collecting PC from a methanol solution (Japanese Patent Unexamined Publication No. Sho. 53-108921/1978); a method of preparing a composition using magnesium lactate and the like (EP394022A1); a method comprising the step of collecting PC from a fermented solution wherein methanol is added to an aqueous solution of PC in a high concentration of about 50 W/V % to adjust a methanol concentration to 90 V/V % (EP822989A1); and a method for preparing PC by using a transformant wherein methanol is added toga PC solution in a high concentration of about 45 to 55 W/W % (EP859848A1).
All of the aforementioned methods involve the use of a mixed solvent of water and an alcoholic solvent such as methanol for crystallization, and are not methods to prepare crystalline PC from a PC solution solely in water. The conventional methods involving the use of methanol for crystallization of PC have a problem of residual methanol, and therefore, it has been desired to develop a method of crystallizing PC from an aqueous solution. However, few attempts have so far been made, since PC is highly dissolvable in water.
An object of the present invention is to provide a method for efficiently preparing nondeliquescent crystalline calcium pantothenate from an aqueous solution of calcium pantothenate which is free from an organic solvent such as methanol, and to provide nondeliquescent crystalline calcium pantothenate which is substantially free from an organic solvent.
The inventors of the present invention made intensive studies to achieve the foregoing objects. As a result, they found that the desired nondeliquescent crystalline calcium pantothenate can be efficiently obtained in an industrial scale by vigorously stirring a supersaturated aqueous solution of calcium pantothenate, which is substantially free from an organic solvent, and drying the resulting viscous crystal suspension. The present invention was achieved on the basis of these findings.
The present invention thus provides a method for preparing nondeliquescent crystalline calcium pantothenate which comprises the steps of: (1) stirring a supersaturated aqueous solution containing calcium pantothenate in a content ratio of 60% (W/W) or more to obtain a suspension of a crystal; and (2) drying the resulting suspension.
According to preferred embodiments of the present invention, provided are the aforementioned method wherein the supersaturated aqueous solution is substantially free from an organic solvent; the aforementioned method wherein a seed crystal of the nondeliquescent crystalline calcium pantothenate is added to the supersaturated aqueous solution in step (1), for example, in a ratio of 0.1% (W/W) or more; the aforementioned method wherein the nondeliquescent crystalline calcium pantothenate is a crystalline substance which comprises xcex1-form crystal, monohydrate, or a mixture thereof; the aforementioned method wherein the supersaturated aqueous solution contains calcium pantothenate in a ratio of from 60% to 74% (W/W); and the aforementioned method wherein the stirring is carried out by using a wet crusher.
From another aspect of the present invention, provided are calcium pantothenate which is obtainable by the aforementioned method; nondeliquescent crystalline calcium pantothenate which is substantially free from an organic solvent; and nondeliquescent crystalline calcium pantothenate which is obtained from a supersaturated aqueous solution of calcium pantothenate which is substantially free from an organic solvent. The present invention also provides calcium pantothenate which contains a crystalline component in an amount sufficient to prevent deliquescence and is substantially free from an organic solvent.
In addition, the present invention provides a supersaturated aqueous solution of calcium pantothenate which contains calcium pantothenate in a ratio of 60% (W/W) or more and is substantially free from an organic solvent. This supersaturated aqueous solution is useful for preparation of the nondeliquescent crystalline calcium pantothenate which is substantially free from an organic solvent. The present invention further provides the aforementioned supersaturated aqueous solution which is used for preparing the nondeliquescent crystalline calcium pantothenate which is substantially free from an organic solvent, and a use of the aforementioned supersaturated aqueous solution for preparing the nondeliquescent crystalline calcium pantothenate which is substantially free from an organic solvent.